The broad objective is to delineate the factors responsible both for establishing and maintaining quaternary structure in subunit- containing enzymes and for allowing the selective binding of inhibitory proteins to enzymes. The genetically well-studied tryptophan synthetase of Escherichia coli and other bacterial cells will be used as a model for the investigation of the effect of single amino acid replacements (point mutation) on homologous (beta-beta chain) and heterologous (alpha-beta chain) subunit interactions. To develop a practical application of methods and insights gained with the bacterial model, an investigation of the natural genetic polymorphism in human serum alpha 1-antitrypsin molecules will be initiated. The effect of naturally occurring variations of the structure of this plentifully produced serine-protease inhibitor will be evaluated from the standpoint of protease-inhibitor recognition, protease-inhibitor affinity, and the enzymatic function of the protease-inhibitor complex. A logical extension of this work will be in the direction of examining the effect of various mutant alpha 1- antitrypsin molecules on the proteases of leucocytes, for the major pathology found in individuals deficient in the amount of alpha 1- antitrypsin is emphysema, thought to result from digestion of lung tissue by unneutralized leucocyte proteases. As there are reported instances of familial emphysema with normal amounts of serum alpha 1- antitrypsin, it is clearly desirable to search for additional genetic polymorphism at both ends of the (leucocyte- protease)-(serum inhibitor) axis.